This ancillary grant application for two years of funding addresses Huntington's disease (HD), a genetic and progressive neurological disorder characterized by a gradual decline in motor, cognitive and behavioral functions. No cure for HD currently exists, and an understanding of disease progression at early stages in the affected brain areas is important for the development of new therapeutic interventions. Recent research has identified the cortico-striatal white matter pathway, which connects the striatum to the motor cortex, as key to HD motor function symptomatology. Current methods of analysis in diffusion MRI, however, are insufficient to properly characterize the pathological changes in this pathway induced by HD. The purpose of this ancillary grant application is therefore to target our novel advanced diffusion MRI biomarkers and analysis methods to the cortico-striatal pathway. By associating abnormalities detected with these novel biomarkers to specific parts of the cortico-striatal tract, it will be possible to precisely map the relationship between white matter tract degeneration and motor dysfunction. This will help advance our understanding of the neuropathological basis of motor deterioration in HD. At the center of this grant proposal is the PREDICT-HD database. This dataset contains brain imaging data and a comprehensive set of clinical correlates from a very large sample of individuals with pre-manifest (prodromal) HD, who were selected to allow for tracing HD symptomatology from its very earliest signs. This proposal will combine the strengths of PREDICT-HD with our cutting-edge neuroimaging technology, which detects and measures several novel types of structural and physiological properties of white matter tissue. The principal innovation in this grant is therefore the use of our novel methods of analysis of diffusion MRI data to characterize in vivo the changes occurring in the white matter connections of the cortico-striatal pathways in HD. Applied together, these new methods will have the ability to not only to quantify pathological changes in white matter, but also to correlate the longitudinal evolution of these changes to the evolution of specific motor dysfunctions. These biomarkers will enhance understanding of pre-manifest HD and will make possible the ability to better monitor disease progression and to target potential early treatments.